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https://www.readbyqxmd.com/read/29165437/endolymphatic-sac-tumour-in-von-hippel-lindau-disease-management-strategies
#1
E Zanoletti, L Girasoli, D Borsetto, G Opocher, A Mazzoni, A Martini
Endolymphatic sac tumour (ELST) is infrequent, as emerges from small series reported in the literature. It is a slow-growing malignancy with local aggressiveness and a low risk of distant metastases. It is often misdiagnosed because of the late onset of symptoms and difficulty in obtaining a biopsy. Its frequency is higher in von Hippel-Lindau (VHL) disease (a genetic systemic syndrome involving multiple tumours), with a prevalence of around 25%. The diagnosis is based on radiology, with specific patterns on contrast-enhanced MRI and typical petrous bone erosion on bone CT scan...
October 2017: Acta Otorhinolaryngologica Italica
https://www.readbyqxmd.com/read/29165391/micrornas-associated-with-von-hippel-lindau-pathway-in-renal-cell-carcinoma-a-comprehensive-review
#2
REVIEW
Lisa-Maria Schanza, Maximilian Seles, Michael Stotz, Johannes Fosselteder, Georg C Hutterer, Martin Pichler, Verena Stiegelbauer
Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time...
November 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29155844/hypoxia-and-hypoxia-inducible-factor-hif-downregulate-antigen-presenting-mhc-class-i-molecules-limiting-tumor-cell-recognition-by-t-cells
#3
Shalini Sethumadhavan, Murillo Silva, Phaethon Philbrook, Thao Nguyen, Stephen M Hatfield, Akio Ohta, Michail V Sitkovsky
Human cancers are known to downregulate Major Histocompatibility Complex (MHC) class I expression thereby escaping recognition and rejection by anti-tumor T cells. Here we report that oxygen tension in the tumor microenvironment (TME) serves as an extrinsic cue that regulates antigen presentation by MHC class I molecules. In support of this view, hypoxia is shown to negatively regulate MHC expression in a HIF-dependent manner as evidenced by (i) lower MHC expression in the hypoxic TME in vivo and in hypoxic 3-dimensional (3D) but not 2-dimensional (2D) tumor cell cultures in vitro; (ii) decreased MHC in human renal cell carcinomas with constitutive expression of HIF due to genetic loss of von Hippel-Lindau (VHL) function as compared with isogenically paired cells with restored VHL function, and iii) increased MHC in tumor cells with siRNA-mediated knockdown of HIF...
2017: PloS One
https://www.readbyqxmd.com/read/29149451/transcriptional-alterations-in-hereditary-and-sporadic-nonfunctioning-pancreatic-neuroendocrine-tumors-according-to-genotype
#4
Xavier M Keutgen, Suresh Kumar, Sudheer Gara, Myriem Boufraqech, Sunita Agarwal, Ralph H Hruban, Naris Nilubol, Martha Quezado, Richard Finney, Maggie Cam, Electron Kebebew
BACKGROUND: Nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited because of germline mutations associated with von Hippel-Lindau disease (VHL) or multiple endocrine neoplasia type 1 (MEN1). The clinical behavior of NFPanNETs is difficult to predict, even in tumors of the same stage and grade. The authors analyzed genotype-specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs to understand the molecular features that determine PanNET phenotype...
November 17, 2017: Cancer
https://www.readbyqxmd.com/read/29146893/von-hippel-lindau-disease-with-multi-organ-involvement-a-case-report-and-8-year-clinical-course-with-follow-up
#5
Ali Yaghobi Joybari, Payam Azadeh
BACKGROUND Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome manifested by a spectrum of benign and malignant tumors.  CASE REPORT The patient presented here was a 31-year-old female with unremarkable family history who presented initially complaining of intermittent abdominal pain. Abdominal CT scan revealed an inhomogeneous solid mass (13×9×7 cm) originating from the tail of the pancreas with splenic and gastric invasion as well as several pancreatic cysts. A nucleotide scan showed left adrenal involvement...
November 17, 2017: American Journal of Case Reports
https://www.readbyqxmd.com/read/29144820/pheochromocytoma-a-genetic-and-diagnostic-update
#6
Leilani B Mercado-Asis, Katherine I Wolf, Ivana Jochmanova, David Taïeb
OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathological studies are performed to prove, localize, treat, and monitor disease progression. Recently, improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (less than 1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment...
November 16, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/29141220/phosphorylation-and-ubiquitination-regulate-protein-phosphatase-5-activity-and-its-prosurvival-role-in-kidney-cancer
#7
Natela Dushukyan, Diana M Dunn, Rebecca A Sager, Mark R Woodford, David R Loiselle, Michael Daneshvar, Alexander J Baker-Williams, John D Chisholm, Andrew W Truman, Cara K Vaughan, Timothy A Haystead, Gennady Bratslavsky, Dimitra Bourboulia, Mehdi Mollapour
The serine/threonine protein phosphatase 5 (PP5) regulates multiple cellular signaling networks. A number of cellular factors, including heat shock protein 90 (Hsp90), promote the activation of PP5. However, it is unclear whether post-translational modifications also influence PP5 phosphatase activity. Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29137356/disruption-of-stat3-dnmt1-interaction-by-sh-i-14-induces-re-expression-of-tumor-suppressor-genes-and-inhibits-growth-of-triple-negative-breast-tumor
#8
Hyo Jin Kang, Yong Weon Yi, Shu-Jie Hou, Hee Jeong Kim, Yali Kong, Insoo Bae, Milton L Brown
Epigenetic regulation of gene expression is an emerging target to treat several human diseases including cancers. In cancers, expressions of many tumor suppressor genes are suppressed by hyper-methylation in their regulatory regions. Herein, we describe a novel carbazole SH-I-14 that decreased the level of the acetyl-STAT3 at the K685 residue. Mutation analysis revealed that SH-I-14 disrupted STAT3-DNMT1 interaction by removing acetyl group from K685 of STAT3. Finally, the inhibition of STAT3-DNMT1 interaction by SH-I-14 resulted in re-expression of tumor suppressor genes such as VHL and PDLIM4 through de-methylation of their promoter regions...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29137006/definition-of-persistent-vomiting-in-current-medical-literature-a-systematic-review
#9
Mostafa Ebraheem Morra, Abdelrahman Elshafay, Aswin Ratna Kansakar, Ghaleb Muhammad Mehyar, Nguyen Phan Hoang Dang, Omar Mohamed Mattar, Somia Iqtadar, Mostafa Reda Mostafa, Vu Ngoc Hai, Tran Le-Huy Vu, Ahmed Abdelmotaleb Ghazy, Fatima Kaboub, Nguyen Tien Huy, Kenji Hirayama
BACKGROUND AND AIM: Persistent vomiting is mentioned as a symptom of a large variety of systemic disorders. It is commonly used interchangeably with chronic, recurrent, or intractable vomiting and widely used as a warning sign of severe illness in dengue infection. However, it has been poorly defined in the medical literature. Therefore, we aimed to systematically review a definition of persistent vomiting in the medical literature. METHODS: A systematic search was done through; PubMed, Google Scholar, Web of Science, Scopus, VHL, WHO-GHL, Grey Literature Report, POPLINE, and SIGLE for the last 10 years...
November 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29134361/sonic-hedgehog-agonist-protects-against-complex-neonatal-cerebellar-injury
#10
Vien Nguyen, Khalida Sabeur, Emin Maltepe, Kurosh Ameri, Omer Bayraktar, David H Rowitch
The cerebellum undergoes rapid growth during the third trimester and is vulnerable to injury and deficient growth in infants born prematurely. Factors associated with preterm cerebellar hypoplasia include chronic lung disease and postnatal glucocorticoid administration. We modeled chronic hypoxemia and glucocorticoid administration in neonatal mice to study whole cerebellar and cell type-specific effects of dual exposure. Chronic neonatal hypoxia resulted in permanent cerebellar hypoplasia. This was compounded by administration of prednisolone as shown by greater volume loss and Purkinje cell death...
November 13, 2017: Cerebellum
https://www.readbyqxmd.com/read/29132830/characterizing-recurrent-and-lethal-small-renal-masses-in-clear-cell-renal-cell-carcinoma-using-recurrent-somatic-mutations
#11
Brandon J Manley, Ed Reznik, Mazyar Ghanaat, Mahyar Kashan, Maria F Becerra, Jozefina Casuscelli, Daniel Tennenbaum, Almedina Redzematovic, Maria I Carlo, Yusuke Sato, Maria Arcila, Martin H Voss, Darren R Feldman, Robert J Motzer, Paul Russo, Jonathan Coleman, James J Hsieh, Ari A Hakimi
INTRODUCTION: Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. METHODS: We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC...
November 10, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/29130501/tert-promoter-hypermethylation-is-associated-with-metastatic-disease-in-abdominal-paraganglioma
#12
Fredrika Svahn, C Christofer Juhlin, Johan O Paulsson, Omid Fotouhi, Jan Zedenius, Catharina Larsson, Adam Stenman
Telomere maintenance, a hallmark of cancer for cell immortalization, is commonly achieved by telomerase activation through induction of the telomerase reverse transcriptase (TERT) gene. Pheochromocytomas (PCC) and abdominal paragangliomas (PGL) (together PPGL) are endocrine tumours for which TERT promoter mutations and telomerase activation have been previously reported [1]. Only 10-15% of PPGL metastasize, however in the absence of metastases, the identification of malignant disease is a diagnostic dilemma...
November 11, 2017: Clinical Endocrinology
https://www.readbyqxmd.com/read/29129718/lessons-in-protac-design-from-selective-degradation-with-a-promiscuous-warhead
#13
Daniel P Bondeson, Blake E Smith, George M Burslem, Alexandru D Buhimschi, John Hines, Saul Jaime-Figueroa, Jing Wang, Brian D Hamman, Alexey Ishchenko, Craig M Crews
Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases...
November 9, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29129716/the-advantages-of-targeted-protein-degradation-over-inhibition-an-rtk-case-study
#14
George M Burslem, Blake E Smith, Ashton C Lai, Saul Jaime-Figueroa, Daniel C McQuaid, Daniel P Bondeson, Momar Toure, Hanqing Dong, Yimin Qian, Jing Wang, Andrew P Crew, John Hines, Craig M Crews
Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors...
October 25, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29126304/sdhc-promoter-methylation-a-novel-pathogenic-mechanism-in-parasympathetic-paragangliomas
#15
Cristóbal Bernardo-Castiñeira, Nuria Valdés, Marta I Sierra, Inés Sáenz-de-Santa-María, Gustavo F Bayón, Raúl F Perez, Agustín F Fernández, Mario F Fraga, Aurora Astudillo, Rafael Menéndez, Belén Fernández, Maribel Del Olmo, Carlos Suarez, María-Dolores Chiara
Context: Germline mutations in the succinate dehydrogenase A, B, C, and D genes (collectively, SDHx) predispose to the development of paragangliomas (PGLs) arising at the parasympathetic or sympathetic neuroendocrine systems. SDHx mutations cause absence of tumoral immunostaining for SDHB. However, negative SDHB-immunostaining has also been found in a subset of PGLs that lack SDHx mutations. Settings: Here, we report the comprehensive molecular characterization of one such a tumor of parasympathetic origin compared with healthy paraganglia and other PGLs with or without SDHx mutations...
November 3, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29126202/activedriverdb-human-disease-mutations-and-genome-variation-in-post-translational-modification-sites-of-proteins
#16
Michal Krassowski, Marta Paczkowska, Kim Cullion, Tina Huang, Irakli Dzneladze, B F Francis Ouellette, Joseph T Yamada, Amelie Fradet-Turcotte, Jüri Reimand
Interpretation of genetic variation is needed for deciphering genotype-phenotype associations, mechanisms of inherited disease, and cancer driver mutations. Millions of single nucleotide variants (SNVs) in human genomes are known and thousands are associated with disease. An estimated 21% of disease-associated amino acid substitutions corresponding to missense SNVs are located in protein sites of post-translational modifications (PTMs), chemical modifications of amino acids that extend protein function. ActiveDriverDB is a comprehensive human proteo-genomics database that annotates disease mutations and population variants through the lens of PTMs...
November 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29124493/genotype-phenotype-correlation-in-asian-indian-von-hippel-lindau-vhl-syndrome-patients-with-pheochromocytoma-paraganglioma
#17
Nilesh Lomte, Sanjeet Kumar, Vijaya Sarathi, Reshma Pandit, Manjunath Goroshi, Swati Jadhav, Anurag R Lila, Tushar Bandgar, Nalini S Shah
The data in genotype-phenotype correlation in Indian von Hippel-Lindau (VHL) patients is limited. We have retrospectively studied 31 genetically proven VHL patients with pheochromocytoma/paraganglioma (PCC/PGL) from families and have reviewed the World literature on PCC/PGL in patients with large VHL deletions. Three patients had large deletions and 28 patients had other mutations [missense mutations in 25, 3 bp deletion in 2 and single bp duplication in one]. Unilateral PCC were significantly more common in patients with large VHL deletions whereas multiple PCC (bilateral PCC or PCC + sympathetic PGL) were significantly more common in those with other mutations...
November 9, 2017: Familial Cancer
https://www.readbyqxmd.com/read/29118224/exceptional-response-to-temsirolimus-in-a-metastatic-clear-cell-renal-cell-carcinoma-with-an-early-novel-mtor-activating-mutation
#18
Juan Francisco Rodríguez-Moreno, María Apellaniz-Ruiz, Juan María Roldan-Romero, Ignacio Durán, Luis Beltrán, Cristina Montero-Conde, Alberto Cascón, Mercedes Robledo, Jesus García-Donas, Cristina Rodríguez-Antona
mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment...
November 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29117921/intralabyrinthine-sporadic-endolymphatic-sac-tumour
#19
C Lucas, J-C Leclère, E Mornet, R Marianowski
INTRODUCTION: Endolymphatic sac tumours are benign, slowly growing tumours that invade the temporal bone, and present clinically in the form of unilateral hearing loss. They can be sporadic or occur in the context of Von Hippel-Lindau disease (VHL). CASE SUMMARY: The authors report a case of endolymphatic sac tumour arising in the utricle presenting histological and immunohistochemical features corresponding to endolymphatic sac tumour in a patient without VHL. DISCUSSION: Endolymphatic sac tumours invade the posterior part of the petrous temporal bone...
November 5, 2017: European Annals of Otorhinolaryngology, Head and Neck Diseases
https://www.readbyqxmd.com/read/29116071/-crispr-cas9-editing-based-modeling-of-hypoxia-in-renal-cancer-cells
#20
N A Zhigalova, S V Zhenilo, A V Artemov, E B Prokhortchouk
Uncontrolled growth in the cell mass of malignant tumors induces intensive angiogenesis. However, the demands of the cancer cells for nutrients and oxygen remain only partially met. Hypoxia is a process that accompanies malignant transformation and evokes changes in the DNA methylation profile in solid tumors. To a certain extent, these changes, including the hypermethylation of tumor suppressor gene promoters, are related to the decrease in the activity of Tet proteins under the conditions of oxygen and free radical deficit...
September 2017: Molekuliarnaia Biologiia
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